α v integrin receptor antagonists

ABSTRACT

The present invention relates to the synthesis of intermediates for the preparation of compounds of formula (A): wherein n is 2 or 3 and various salt forms of these compounds. The compounds of formula (A) are useful as ανβ3 receptor antagonists

FIELD OF THE INVENTION

The present invention relates to chemical compounds, their use asintermediates in the preparation of pharmaceutical agents, and toprocesses for their preparation.

BACKGROUND OF THE INVENTION

International Patent Publication No. WO 00/72801 discloses a series of3-substituted nonanoic acid derivatives of use as ανβ3 receptorantagonists, including compounds of the formula (A):

wherein n is 2 or 3.

The synthetic methods given in that application work well on a smallscale, but the process is linear and requires a chiral HPLC separationof enantiomers of a penultimate intermediate. The δ-keto-acid moietywithin the compound of formula (A) contains the only stereogenic carbon.There is therefore a need for an enantioselective and more efficientsynthetic route to the compound of formula (A).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an x-ray powder diffraction (XRPD) pattern for the Form Apolymorph of the product of Example 5 containing all observed XRPDreflections between 3° and 40° 2-theta. The ordinate or Y-axis is x-rayintensity (counts) and the abscissa or X-axis is the angle two-theta(2θ) in degrees.

FIG. 2 is an x-ray powder diffraction (XRPD) pattern for the Form Bpolymorph of the product of Example 5 containing all observed XRPDreflections between 3° and 40° 2-theta. The ordinate or Y-axis is x-rayintensity (counts) and the abscissa or X-axis is the angle two-theta(2θ) in degrees.

FIG. 3 is an x-ray powder diffraction (XRPD) pattern for the crystallinezwitterion of the compound of formula (A) where n=3 containing allobserved XRPD reflections between 3° and 40° 2-theta. The ordinate orY-axis is x-ray intensity (counts) and the abscissa or X-axis is theangle two-theta (2θ) in degrees.

FIG. 4 is an x-ray powder diffraction (XRPD) pattern for the crystallineTRIS salt of the compound of formula (A) where n=3 containing allobserved XRPD reflections between 3° and 40° 2-theta. The ordinate orY-axis is x-ray intensity (counts) and the abscissa or X-axis is theangle two-theta (2θ) in degrees.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of general formula (I):

wherein n is 2 or 3, P is an amino protecting group and R¹ is hydrogen,chlorine, bromine or C₁ to C₆ straight or branched alkyl, are usefulintermediates.

The present invention also provides a method of preparing a compound offormula (I) which comprises the ring closure of a compound of theformula (II):

wherein R¹, P and n are as defined in relation to formula (I) and Y is achlorine, bromine or iodine atom or a mesylate, tosylate, brosylate,nosylate or triflate group.

Preferably this reaction is carried out in the presence of a coppercatalyst such as CuCl, CuBr, CuBr.Me₂S, CuI, and the like.

The compounds of formula (II) may be prepared by the reaction of acompound of the formula (III):

wherein R¹ and P are as defined in relation to formula (II) and R³ ishydrogen or methyl with a C₁₋₆-alkyl lithium, such as hexyllithium,n-butyllithium and sec-butyllithium, followed by reaction with acompound of the formula (IV):X—(CH₂)_(m)—Y  (IV)wherein Y is defined as in relation to formula (II), X is a chlorine,bromine or iodine atom or a mesylate, tosylate, brosylate, nosylate ortriflate group, and m is 3 or 4 when R³ is hydrogen, or m is 2 or 3 whenR³ is methyl.

It is a great advantage of the present invention that the abovereactions may be performed as a “one pot” or single stage reaction.

In formulae (I), (II) and (III), R¹ is preferably a chlorine atom.

In formulae (I) and (II), n is most aptly 3.

In formulae (I), (II) and (III), suitable examples of the aminoprotecting group P include a group selected from:tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl, trimethylsilyl,triethylsilyl, acetyl, pivaloyl (2,2-dimethyl-1-oxopropyl),o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl,tert-butyloxycarbonyl (t-BOC), 2,2,2-trichloroethyloxycarbonyl,benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl,2,2,2-trichloroethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,2-(trimethylsilyl)ethyl, p-methoxybenzyl, p-methoxyphenyl,4-pyridylmethyl, tert-butyl, allyloxycarbonyl, di-C₁₋₁₀ alkylphosphoryl,diarylphosphoryl and di-ar-C₁₋₁₀ alkylphosphoryl.

More particularly, P represents a protecting group which is selectedfrom the group consisting of: an alkoxycarbonyl group (especiallyt-BOC), diisopropylphosphoryl and pivaloyl (2,2-dimethyl-1-oxopropyl).

Most suitably, P is a tert-butoxycarbonyl (t-BOC) group.

Hence, in a favoured embodiment, the present invention provides aprocess for the preparation of the compounds of the formulae (V) and(VI):

which comprises the reaction of a compound of the formula (IV) asdefined above with the compound of the formula (VII)

to yield a compound of the formula (VIII)

wherein Y is as defined in relation to formula (II) and p is 3 or 4, andwhich is cyclised, without isolation, to the compounds of formulae (V)and (VI), respectively.

In compounds of formula (IV), X and Y are suitably both halogen, forexample X may be bromo or iodo and Y may be chloro. Apt compoundsinclude Cl(CH₂)₄I, Cl(CH₂)₃I, Cl(CH₂)₂I, Cl(CH₂)₄Br, Cl(CH₂)₃Br andCl(CH₂)₂Br.

The compounds of the formulae (III) and (VII) may be prepared from thecorresponding carbamates of formulae (IX) and (X), wherein BOC is CO₂^(t)Bu:

by reaction with a lithium alkyl such as a slight excess of n-BuLi ors-BuLi preferably in the presence of equimolar amount oftetramethylethylenediamine.

The compounds of formula (I) may be converted into compounds ofInternational Patent Publication No. WO 00/72801 by the syntheticmethods described therein and by other conventional chemical syntheticmethods.

The compounds of formula (I) are also useful intermediates in thepreparation of compounds of U.S. Pat. No. 3,960,876 and can be used asdescribed therein.

The present invention further describes a practical method to prepareenantiopure compounds of the formula (XI):

and salts thereof wherein R is an esterifying group. Most suitably, R isa C₁₋₆ alkyl group such as methyl, ethyl or propyl group and ispreferably a methyl group.

Compounds of formula (XI) may be prepared by the asymmetric solvolysisof the anhydride of the formula (XII):

This reaction may be performed using lower alkanols such as methanol,ethanol, 2,2,2-trifluoroethanol, 1-propanol, benzyl alcohol, 2-propanoland 1,1,1,3,3,3-hexafluoro-2-propanol at a temperature between −70° C.and ambient temperature. Preferably, the reaction is carried out withmethanol at about −30° C. The reaction will use a solvent which can bean excess of the lower alkanol but which is preferably an inert solventsuch as THF, DMF, dichloromethane or toluene. Generally about 10equivalents of the alkanol will be used and the reaction adjusted to aconcentration of about 0.2-0.4 M. The reaction is performed in thepresence of a catalytic or stoichiometric amount of an optically activeamine. The amine is typically a naturally occurring Cinchona alkaloid orone of its derivatives and is most suitably present in an equimolaramount. Preferred amines include quinidine and quinine. Hence thecompound of formula (XIa) is favourably formed as the quinidine salt. Onthe other hand, the compound of formula (XIb) can be obtained withquinine. It is an important advantage of the current invention that thediastereomeric purity of the amine salts can in principle beconveniently increased via a recrystallization.

This invention also provides a practical procedure to prepare thecompound of formula (m as well as methods to convert compounds of theformula (XIa) or (XIb) into compounds of the formula (XIII):

wherein R is as defined in relation to formula (XI) and X is (a) a—CH₂P(O)(OR′)₂ group, wherein R′ is defined as a C₁₋₆alkyl group such asmethyl, ethyl, propyl, isopropyl, etc. or (b) a Ph₃P═CH— group.

The compounds of formula (XIIIa) wherein X is —CH₂P(O)(OR′)₂ may beprepared from the compounds of formula (XIa) by an activation reactionwith pivaloyl chloride and triethylamine in dry THF at −5° C., yieldinga compound of formula (XIII) wherein X is —O.CO.C(CH₃)₃, followed by areaction with an excess of lithiated dialkylmethylphosphonate at lowtemperature. Alternatively, compounds of formula (XIIIa) can be preparedby a reaction of compounds of the formula (XIb) with an excess oflithiated dialkylmethylphosphonate at low temperature followed by anesterification.

The compound of formula (XIIIb) wherein X is Ph₃P═CH— may be preparedfrom the compounds of formula (XIa) by an activation reaction witheither pivaloyl chloride or isobutylchloroformate and a suitable base(triethylamine, diisopropylethylamine, etc.) in dry THF at about −5° C.,yielding compounds of formula (XIII) wherein X is —O.CO.C(CH₃)₃ and—OCO₂ ^(i)Bu, respectively, followed by a reaction with an excess oflithiated Ph₃P^(⊕)CH₃.Br^(⊖) in THF at about −70° C. and then allowingthe reaction to warm to ambient temperature. The excess lithiatedPh₃P^(⊕)CH₃.Br^(⊖) can range from 2.2 to 3.5 equivalents depending onwhether or not the triethylamine hydrochloride salt which is formed inthe activation step is removed (via filtration or extraction).

The compounds of formulae (XI) and (XIII) are at least 60%enantiomerically pure, more suitably at least 80% enantiomerically pure,preferably at least 90% enantiomerically pure and most preferably atleast 98% enantiomerically pure.

The compound of formula (XII) may be prepared by treating thecorresponding diacid of formula (XIV)

with trifluoroacetic anhydride in a suitable inert solvent, such as THFat an elevated temperature, such as between 50 and 55° C.Crystallisation by slow addition of an antisolvent, such as heptanefollowed by cooling, for instance to ambient temperature, results ingood yield.

The diacid of formula (XIV) may be prepared by reacting2-methoxypyrimidine-5-carbaldehyde with ethylacetoacetate in thepresence of piperidine in a suitable solvent, such as an alcohol, forexample, propan-2-ol, at a temperature in the range of 10-80° C.,preferably at 50° C. The reaction is followed by a hydrolysis with, forinstance, aqueous sodium hydroxide at 0° C., phase separation of theresulting mixture, acidification of the aqueous layer with, forinstance, concentrated hydrochloric acid to pH 2-3 and crystallizationof the product.

The compounds of the formulae (XIIIa) and (XIIIb) are usefulintermediates to prepare the compound of formula (A) via a reaction withthe compound of formula (XV)

and further elaboration of the resulting product to give the desiredactive pharmaceutical ingredient.

The present invention further describes a practical method to prepareenantiopure compounds of the formula (A) which comprises reacting acompound of formula (XVI) with a compound of formula (XIII):

wherein n is 2 or 3, P is an amino protecting group, and R and X are ashereinbefore defined for the compound of formula (XIII); followed byenone reduction and deprotection of the carboxyl and amino groups.

Preferably n is 3.

Suitable examples of the amino protecting group P include a groupselected from: tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl,trimethylsilyl, triethylsilyl, acetyl, pivaloyl(2,2-dimethyl-1-oxopropyl), o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, tert-butyloxycarbonyl(t-BOC), 2,2,2-trichloroethyloxycarbonyl, benzhydryl, o-nitrobenzyl,p-nitrobenzyl, 2-naphthylmethyl, benzyl, 2,2,2-trichloroethyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl,2-(trimethylsilyl)ethyl, p-methoxybenzyl, p-methoxyphenyl,4-pyridylmethyl, tert-butyl, allyloxycarbonyl, di-C₁₋₁₀ alkylphosphoryl,diarylphosphoryl and di-ar-C₁₋₁₀ alkylphosphoryl.

More particularly, P represents a protecting group which is selectedfrom the group consisting of: an alkoxycarbonyl group (especiallyt-BOC), diisopropylphosphoryl and pivaloyl (2,2-dimethyl-1-oxopropyl).

Most suitably, P is a tert-butoxycarbonyl (t-BOC) group.

Most suitably, R is a C₁₋₆ alkyl group such as methyl, ethyl or propylgroup and is preferably a methyl group.

Preferably, X is —CH═PPh₃.

The reaction is conveniently effected as a single solventthrough-process. Suitable solvents include toluene, isopropyl acetate,acetonitrile, ethanol and isopropyl alcohol (2-propanol), the latterbeing most preferred.

Conveniently, the intermediate enone of formula (XVII)

is not isolated. Enone reduction is conveniently effected byhydrogenation in the presence of a palladium metal catalyst, aptlypalladium on carbon. After filtration of the catalyst, a saponificationstep using aqueous hydroxide, for example, sodium hydroxide, removes thecarboxyl protecting group to give the compound of formula (XVIII)

Deprotection of compound (XIII) can be effected in a conventionalmanner. Preferably, when P is a tert-butoxycarbonyl (BOC) group, acidsare used. Most preferably, a treatment with an excess of trifluoroaceticacid (preferably about 15 equivalents) is used. The reaction is effectedin a suitable solvent. Preferably, a halogenated hydrocarbon, forexample, dichloromethane, at a temperature between 20° C. and 40° C. isused.

After neutralizing the reaction mixture with aqueous hydroxide, forexample, sodium hydroxide, and, if necessary, adjusting the pH of theseparated aqueous layer to about 6.0 using a mineral acid, such ashydrochloric acid, the compound of formula (A) is extracted as thezwitterion using a suitable solvent, preferably dichloromethane.

Before or after deprotection of the amino moiety, the reaction mixturemay undergo a carbon treatment to reduce the level of residualpalladium.

The compound of formula (A) may be crystallized from a lower alkanolsolvent. Ethanol and 2-propanol are the preferred solvents; 2-propanolis the most preferred solvent.

The novel, crystalline zwitterion of the compound of formula (A) isunexpectedly stable and non-hygroscopic, and has a desirable watersolubility making it particularly advantageous for pharmaceuticalformulation. The crystalline zwitterion of the compound of formula (A)where n=3 is characterised by the X-ray powder diffraction (XRPD) datashown in FIG. 3, which has the significant peaks listed in Table 1:

TABLE 1 Angle d value Intensity 2-Theta ° Angstrom Count 9.8 8.98 40815.1 5.86 439 15.5 5.73 331 16.4 5.40 151 17.3 5.13 160 18.1 4.89 13819.8 4.48 278 22.1 4.01 965 23.5 3.78 247 24.6 3.61 202 27.3 3.27 176

Although crystalline zwitterion of the compound of formula (A) where n=3is characterized by the complete group of angle 2 theta values listed inTable 1, all the values are not required for such identification. Thecrystalline zwitterion of the compound of formula (A) where n=3 can beidentified by the most significant angle 2 theta values: 9.8°, 15.1°,15.5°, 19.8°, 22.1°, 23.5° and 24.6°.

The compound of formula (A) may also be crystallized as thetris(hydroxymethyl)aminomethane (TRIS) salt by treating a solution ofthe zwitterion (for instance, in 2-propanol) withtris(hydroxymethyl)aminomethane and then crystallizing the TRIS saltfrom either ethanol or, more preferably, 2-propanol. The crystallizationsolvent may be “wet” or “dry”, i.e. containing a water content ofbetween about 6% and less than 0.1%, preferably about 4%.

The novel, crystalline TRIS salt of the compound of formula (A) wheren=3 is characterised by the XRPD data shown in FIG. 4, which has thesignificant peaks listed in Table 2:

TABLE 2 Angle d value Intensity 2-Theta ° Angstrom Count 5.3 16.56 42215.4 5.76 102 16.1 5.51 259 20.2 4.39 227 21.5 4.13 633 22.1 4.01 147

Although crystalline TRIS salt of the compound of formula (A) where n=3is characterized by the complete group of angle 2 theta values listed inTable 2, all the values are not required for such identification. Thecrystalline TRIS salt of the compound of formula (A) where n=3 can beidentified by the most significant angle 2 theta values: 5.3°, 16.1°,20.2° and 21.5°.

If desired, the crystallization of the TRIS salt of the compound offormula (A) may be utilised in a method of purifying the zwitterion ofthe compound of formula (A). Thus, the zwitterion is prepared aspreviously described, and is converted to the TRIS salt as describedabove. After recovery of the crystalline TRIS salt, the salt is brokenby dissolving the TRIS salt in de-ionized water. The pH is adjusted toabout 6.0 using, for example, hydrochloric acid, and the solutionextracted with dichloromethane. After washing with further de-ionizedwater, the solvent is switched and the product crystallized as describedabove.

If desired, a carbon treatment stage may be incorporated into thezwitterion recrystallization using a suitable carbon.

The crystalline zwitterion compound of formula (A) prepared in the abovemethod has a very high enantiopurity, with an enantiomeric excess of≧98%, preferably ≧99%, and more preferably ≧99.5%.

According to a further aspect of the present invention, compounds offormula (XVI) may be prepared by a Suzuki coupling of the compounds offormulae (I) and (XIX), wherein R¹ is a chlorine atom and each R^(a) isindependently C₁ to C₆ straight or branched alkyl, preferably methyl orethyl and P is defined as above,

followed by acetal hydrolysis to yield the compound of formula (XVI).

Conditions suitable for a Suzuki coupling reaction are well known in theart (for review, see for instance A. Suzuki, in “Metal-catalyzedCross-coupling Reactions”, F. Diederich and P. J. Stang (Eds.),Wiley-VCH; Weinheim (1998), pp 49-89), using a catalyst formed in situfrom a suitable palladium salt and a ligand. Suitable catalysts includetetrakis(triphenylphosphine)palladium (0), the combination ofpalladium(II) acetate and 1,1′-bis(diphenylphosphanyl)ferrocene (DPPF)or the related dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, or the combination of palladium(II) acetateand tricyclohexylphosphine (Cy₃P), or the relatedbis(tricyclohexylphosphine)-palladium (0) ortrans-dichlorobis(tricyclohexylphosphine)palladium (II).

A particularly preferred catalyst is that formed in situ from acombination of palladium(II) acetate and1,1′-bis(diphenylphosphanyl)ferrocene (DPPF).

The reaction is effected in the presence of a base, for example,potassium carbonate, sodium tert-butoxide or aqueous sodium hydroxide,in a suitable solvent such as an ether, for example, tetrahydrofuran,dimethoxyethane or dioxane or an aromatic hydrocarbon, for exampletoluene, and at an elevated temperature, for example, between 65° C. andthe reflux temperature of the solvent.

A particularly preferred base is potassium carbonate.

Immediately following the coupling reaction acetal hydrolysis can beeffected in high yield using conventional procedures, for example, byextracting the diethyl acetal intermediate into isopropyl acetate andtreating with a strong acid such as hydrochloric acid, at a reducedtemperature, for example, between 0° C. and 10° C.

The compound of formula (XIX) can be prepared from the commerciallyavailable acrolein dialkyl acetal, preferably the diethyl or dimethylacetal, and 9-borabicyclo[3.3.1]nonane (9-BBN) following a standardhydroboration protocol at 0 to 30° C. in an ether solvent, preferablytetrahydrofuran.

The compound of the formula (III) where R¹ is a chlorine atom may alsobe prepared from the corresponding protected amine of formula (XX)

by reaction with a lithium alkyl such as a slight excess of n-BuLi ors-BuLi, preferably in the presence of an equimolar amount oftetramethylethylenediamine.

The following non-limiting examples are provided to illustrate thepresent invention.

EXAMPLE 1 1,1-Dimethylethyl2-chloro-5,6,7,8-tetrahydro-9H-pyrido[2,3-b]azepine-9-carboxylate

Tetramethylethylenediamine (5.85 kg) was dissolved in THF (54.5 L) anddegassed. The bath was cooled to −20° C. and then hexyllithium (˜2.5 M,22 L) was charged over 35 minutes maintaining the internal temperaturebetween −10° C. and −20° C. The batch was aged for 30 minutes between−18° C. to −16° C. and then cooled further to −75° C. A solution of1,1-dimethylethyl[6-chloro-2-pyridinyl]carbamate (5.23 kg) in THF (16 L)was added to the above solution, maintaining the temperature below −65°C. The red/brown dianion solution was aged for 1 hour at −70° C. andthen a solution of 1-chloro-4-iodobutane (7.57 kg) in THF (5 L) wasadded, maintaining the internal temperature below −65° C. After theaddition, the reaction was allowed to warm slowly to ambient temperatureand then heated to reflux for 9 hours. The solution was then cooled to60° C. and water (54.5 kg) added, maintaining the internal temperatureabove 40° C. The aqueous layer was cut and extracted with isopropylacetate (IPAc) (54.4 L). The combined organic layers were washed withwater (27 L), azeotropically distilled iin vacuo to a volume of 26 L,and then solvent switched to heptane to a final volume of 26 L. Theresulting slurry of crystals was cooled to 5° C., aged for 1 hour andthen isolated by filtration. A wash with cold heptane (10 L) andovernight drying iin vacuo at 40° C. furnished the title compound (5.05kg) in 78% yield. Recrystallisation from ethyl acetate furnished ananalytically pure sample; m.p. 166-168° C.

¹H NMR (400 MHz, d₆-DMSO, 343 K): δ 7.62 (d, J=7.9 Hz, 1H), 7.17 (d,J=7.9 Hz, 1H), 3.35 (m, 2H), 2.58 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H),1.22 (s, 9H); ¹³C NMR (100 MHz, d₆-DMSO, 343 K): δ 155.7, 153.8, 146.7,142.8, 134.0, 123.3, 80.6, 47.1, 32.6, 29.5, 28.8, 25.7.

EXAMPLE 2

In all of the following reactions high yielding lithiation could beachieved by the addition of 1 b to a slight excess (2.2 eq) of anequimolar TMEDA/n-BuLi solution, whereas the lithiation of 1 a requiredmore forcing conditions (TMEDA/n-BuLi at −10° C. or TMEDA/s-BuLi at −78°C.). The TMEDA/BuLi mixtures were aged for about 30 minutes at −20° C.prior to addition of substrate 1. The dianion is then quenched with theα,ω-dihalide to form the intermediate. Warming the reaction mixture toreflux effected ring closure to give the product 2. The results of aseries of experiments were as follows:

TABLE 3

Copper (I) Yield Entry Substrate 1 R—Li Additive Halide ElectrophileProduct 2 %^(a)  1 1a s-BuLi TMEDA — Cl(CH₂)₂I 2a  0  2 1a s-BuLi TMEDA— Cl(CH₂)₃I 2c 54  3 1a s-BuLi TMEDA — Cl(CH₂)₄I 2e 55  4 1d n-BuLi — —Cl(CH₂)₂I 2d  0  5 1c n-BuLi — — Cl(CH₂)₃I 2e 86  6 1c n-BuLi — —Cl(CH₂)₂Br 2c  0  7 1b n-BuLi TMEDA — Cl(CH₂)₄Br 2f 51  8 1b n-BuLiTMEDA — Cl(CH₂)₃I 2d 51  9 1b n-BuLi TMEDA — Cl(CH₂)₄I 2f 85 10 1bn-BuLi TMEDA — MeI 1d 91 11 1b n-BuLi TMEDA CuCl Cl(CH₂)₃I 2d 95 (91) 121b n-BuLi TMEDA CuBr Cl(CH₂)₃I 2d 94 13 1b n-BuLi TMEDA CuBr•Me₂SCl(CH₂)₃I 2d 94 14 1b n-BuLi TMEDA CuI Cl(CH₂)₃I 2d 98 15 1b n-BuLiTMEDA CuBr•Me₂S Cl(CH₂)₄I 2f 90 (86) 16 1b n-BuLi TMEDA CuBr Cl(CH₂)₂I2b 57 17 1b n-BuLi TMEDA CuBr•Me₂S Cl(CH₂)₂I 2b 57 ^(a)Yield refers toHPLC assay yield, obtained by comparison with an isolated pure standard.Yield in parentheses refers to isolated yield, either by silica gelchromatograph or crystallisation.

EXAMPLE 3 4-Carboxy-3-(2-methoxypyrimidin-5-yl)butanoic acid

2-Methoxypyrimidine-5-carbaldehyde (see J. Heterocycl. Chem. (1991) 28,1281) (9.00 kg) was reacted with ethylacetoacetate (17.8 kg) in thepresence of piperidine (555 g) in propan-2-ol (90 L) at 50° C. forseveral hours, followed by a hydrolysis with aqueous sodium hydroxide(24.2 kg of 46% NaOH in 30 L of water) at 0° C. Phase separation of theresulting mixture, acidification of the aqueous layer with concentratedhydrochloric acid (23.2 kg) to pH 2-3 and crystallization afforded thetitle compound (12.7 kg; 85% yield).

¹H NMR (250 MHz, methanol-d₄) δ 8.52 (s, 2 H), 3.98 (s, 3 H), 3.54 (tt,J=9.2, 6.1 Hz, 1H), 2.82 (dd, J=16.2, 6.1 Hz, 2 H), 2.67 (dd, J=16.2,9.2 Hz, 2 H); ¹³C NMR 63 MHz, methanol-d₄) δ 174.9, 165.9, 160.2, 131.4,55.6, 40.5, 34.6.

EXAMPLE 4 4-(2-Methoxypyrimidin-5-yl)glutaric anhydride

4-Carboxy-3-(2-methoxypyrimidin-5-yl)butanoic acid (11.5 kg) was treatedwith trifluoroacetic anhydride (12.1 kg) in THF (58 L) at 50-55° C. forseveral hours. Slow addition of heptane (195 L) followed by cooling toambient temperature resulted in the crystallization of the titlecompound; 94% yield.

¹H NMR (250 MHz, CD₂Cl₂) δ 8.41 (s, 2 H), 3.99 (s, 3 H), 3.49-3.35 (m, 1H), 3.18-3.07 (m, 2 H), 2.92-2.79 (m, 2 H); ¹³C NMR (63 MHz, CD₂Cl₂) δ165.3, 164.9, 157.4, 125.6, 54.8, 36.2, 29.2.

EXAMPLE 5 (3S)-4-(Methoxycarbonyl)-3-(2-methoxypyrimidin-5-yl)butanoicacid

Toluene (180 L) was charged to a vessel containing anhydride (XII) (9.0kg) and quinidine (13.15 kg) under a nitrogen atmosphere. The resultingslurry was cooled, with stirring, to −40° C. Methanol (13.0 kg), whichhad been pre-cooled to approx. 5° C., was then added over 15 minutes.The resulting reaction mixture was held at about −35° C. for 8 hours andthen allowed to warm to ambient temperature overnight.

The reaction mixture was then extracted twice with water (2×60 L). Thecombined aqueous extracts were acidified with concentrated hydrochloricacid (4.0 kg), then seeded with the authentic product (45 g) beforeanother portion of concentrated hydrochloric acid (4.0 kg) was added.The temperature of the resulting slurry was adjusted to 20° C., aged for2 hours and then filtered to afford 6.54 kg of 98% e.e. pure crystallineproduct (63% yield).

¹H NMR (250 MHz, methanol-d₄) δ 8.52 (s, 2 H), 3.98 (s, 3 H), 3.62-3.48(m, 1 H), 3.59 (s, 3 H), 2.85 (dd, J=16.2, 11.6 Hz, 1 H), 2.82 (dd,J=16.3, 11.7 Hz, 1 H), 2.73 (dd, J=16.2, 9.0 Hz, 1 H), 2.67 (dd, J=16.2,9.0 Hz, 1 H); ¹³C NMR (63 MHz, methanol-d₄) δ 174.8, 173.5, 165.9,160.2, 131.3, 55.6, 52.3, 40.4, 40.4, 34.6.

Two polymorphic crystal forms of (XIa) have been identified. Form A ischaracterized by a melting point of 148° C. and having an XRPD patternat (FIG. 1), which has the significant peaks listed in Table 4:

TABLE 4 Angle d value Intensity 2-Theta ° Angstrom Count 9.4 9.40 68614.2 6.23 727 14.6 6.04 633 15.1 5.88 280 18.2 4.88 193 19.5 4.55 85019.9 4.46 249 22.2 4.00 246 23.1 3.85 2009 26.7 3.33 2221 28.4 3.14 167430.4 2.94 244Form B is characterized by a melting point of 145° C. and having an XRPDpattern at (FIG. 2), which has the significant peaks listed in Table 5:

TABLE 5 Angle d value Intensity 2-Theta ° Angstrom Count 12.5 7.10 43513.0 6.81 1289 13.7 6.45 158 16.9 5.24 241 21.2 4.18 1008 22.9 3.88 100223.7 3.74 2306 29.4 3.03 394

EXAMPLE 6 Methyl(3S)-3-(2-methoxypyrimidin-5-yl)-5-oxo-6-(triphenylphosphoranylidene)hexanoate

A suspension of methyltriphenylphosphonium bromide (18.2 kg) in THF (82L) was cooled to −60° C. Hexyllithium (13.8 kg) was-then added over 30minutes, while keeping the internal temperature below −10° C. Once theaddition was complete, the batch was aged at 0° C. for 90 minutes andthen cooled to −80° C. and held awaiting the mixed anhydride formation.

A solution of acid-ester (XI) (4.38 kg) and trimethylacetyl chloride(2.06 kg) in THF (34 L) was cooled to −5° C. and triethylamine (1.72 kg)was added over a period of 30 minutes. After a rinse with THF (0.5 L),the resulting slurry was aged between −5 and 0° C. for 30 minutes andthen added to the above ylide mixture whilst maintaining the internaltemperature at approximately −70° C. The mixed anhydride vessel wasrinsed with THF (8 L) and this rinse was also added to the batch.

After an age of 40 minutes the reaction mixture was transferred into anaqueous solution of potassium dihydrogenphosphate (1.20 kg KH₂PO₄ in 64L of water), keeping the temperature of the quenched mixture between 0and 10° C. Isopropyl acetate (IPAc) (85 L) was added to the quenchedreaction mixture and the two phases were separated. The aqueous layerwas further extracted with IPAc (85 L) and the combined organic extractswere then washed twice with half-saturated brine (6.95 kg NaCl in 38 Lof water, each). The resulting organic layer was concentrated underreduced pressure to a volume of 25 L. IPAc (34 L) was added and thebatch was again concentrated until a final volume of 25 L was reached.Crystallization of the product had occurred during this distillationand, after cooling to 0° C., the solid was collected by filtration,washing the wet-cake with MTBE (10.5 L). Drying overnight, under vacuum,at 30° C. afforded 6.28 kg of phosphorane (XIIIb) (70% corrected yield)as cream-coloured crystals.

¹H NMR (250 MHz, CD₂Cl₂) δ 8.33 (s, 2 H), 7.52-7.28 (m, 15 H), 3.88 (s,3 H), 3.60-3.48 (m, 2 H), 3.47 (s, 3 H), 2.70 (dd, J=15.7, 5.9 Hz, 1 H),2.58-2.45 (m, 3 H); ¹³C NMR (63 MHz, CD₂Cl₂) δ 189.3 (d, J=2 Hz), 172.4,165.0, 159.1, 133.3 (d, J=10 Hz), 132.5 (d, J=3 Hz), 130.6, 129.1 (d,J=12 Hz), 127.3 (d, J=91 Hz), 55.0, 53.2 (d, J=107 Hz), 51.8, 46.8 (d,J=16 Hz), 40.7, 34.8.

EXAMPLE 7 1,1-Dimethylethyl2-chloro-5,6,7,8-tetrahydro-9H-pyrido[2,3-b]azepine-9-carboxylate

Tetramethylethylenediamine (5.85 kg) was dissolved in THF (54.5 L) anddegassed. The bath was cooled to −20° C. and then hexyllithium (˜2.5 M,22 L) was charged over 35 minutes maintaining the internal temperaturebetween −10° C. and −20° C. The batch was aged for 30 minutes between−18° C. to −16° C. and then cooled further to −75° C. A solution of1,1-dimethylethyl[6-chloro-2-pyridinyl]carbamate (5.23 kg) in THF (16 L)was added to the above solution, maintaining the temperature below −65°C. The red/brown dianion solution was aged for 1 hour at −70° C. andthen a solution of 1-chloro-4-iodobutane (7.57 kg) in THF (5 L) wasadded, maintaining the internal temperature below −65° C. After theaddition, the reaction was allowed to warm slowly to ambient temperatureand then heated to reflux for 9 hours. The solution was then cooled to60° C. and water (54.5 kg) added, maintaining the internal temperatureabove 40° C. The aqueous layer was cut and extracted with IPAc (54.4 L).The combined organic layers were washed with water (27 L),azeotropically distilled in vacuo to a volume of 26 L, and then solventswitched to heptane to a final volume of 26 L. The resulting slurry ofcrystals was cooled to 5° C., aged for 1 hour and then isolated byfiltration. A wash with cold heptane (10 L) and overnight drying invacuo at 40° C. furnished the title compound (5.05 kg) in 78% yield.Recrystallisation from ethyl acetate furnished an analytically puresample; m.p. 166-168° C.

¹H NMR (400 MHz, d₆-DMSO, 343 K): δ 7.62 (d, J=7.9 Hz, 1H), 7.17 (d,J=7.9 Hz, 1H), 3.35 (m, 2H), 2.58 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H),1.22 (s, 9H); ¹³C NMR (100 MHz, d₆-DMSO, 343 K): δ 155.7, 153.8, 146.7,142.8, 134.0, 123.3, 80.6, 47.1, 32.6, 29.5, 28.8, 25.7.

EXAMPLE 8 tert-Butyl2-(3-oxopropyl)-5,6,7,8-tetrahydropyrido[2,3-b]azepine-9-carboxylate

Acrolein diethyl acetal (3.51 kg) was added over 30 minutes to 0.41 M9-BBN in THF (57.4 L) which had been pre-cooled to 0° C. The resultingreaction mixture was warmed to room temperature and then aged for 5hours to give the hydroborated acrolein acetal.

A suspension of 1,1-dimethylethyl2-chloro-5,6,7,8-tetrahydro-9H-pyrido[2,3-b]azepine-9-carboxylate (3.32kg), potassium carbonate (3.25 kg), palladium acetate (132 g) and1,1′-bis(diphenylphosphanyl)ferrocene (dppf) ((326 g) in THF (16.5 L)was degassed and put under an atmosphere of nitrogen. The THF solutionof the hydroborated acrolein acetal was then added. The reaction mixturewas degassed, purged with nitrogen and then heated at reflux for 26hours. The reaction mixture was then cooled to 20° C., water (66 L) wasadded and the mixture was stirred for 30 minutes. The two layers wereallowed to settle and the lower aqueous phase was discarded. IPAc (10 L)was then added and, after stirring for 5 minutes and allowing themixture to settle, the lower aqueous phase was again discarded. Theresulting organic layer was concentrated by distillation under reducedpressure to minimum volume (55 L of distillate removed) and a secondportion of IPAc (33 L) was then charged. The two layers were againseparated, the aqueous phase was discarded and the remaining organiclayer was concentrated to minimum volume (10 L) under reduced pressure.IPAc (23 L) was added and the mixture held overnight at ambienttemperature. The solution was cooled to 0° C. and treated withpre-cooled (0° C.) 2M hydrochloric acid (23.0 L), while keeping thetemperature below 10° C. The resulting two phase mixture was stirred at0° C. for 4 hours.

The mixture was allowed to settle and the phases separated. The aqueousphase was filtered, cooled to 0-5° C. and IPAc (16.5 L) added. Themixture was then basified (to pH 8) by addition of 10% aqueous potassiumcarbonate (5.5 kg dissolved in 49.5 L of water). The mixture wasagitated for 5 minutes, allowed to settle and the phases separated. Theaqueous phase was extracted with IPAc (2×16.5 L) and the combined IPAcextracts were washed with water (8.25 L). The IPAc solution wasconcentrated by distillation under reduced pressure to low volume (ca.10 L). Isopropanol (33 L) was added and the solution again distilled tolow volume under reduced pressure. Additional isopropanol (33 L) wasadded and the solution concentrated to about 15 L by distillation underreduced pressure. The isopropanol solution was then assayed for thedesired aldehyde (yield: 3.075 kg; 86%).

EXAMPLE 9 tert-Butyl2-[(7S)-8-methoxycarbonyl-7-(2-methoxypyrimidin-5-yl)-5-oxo-3-octenyl]-5,6,7,8-tetrahydropyrido[2,3-b]azepine-9-carboxylate

A solution of the priopionaldehyde of Example 8 (3.02 kg) in isopropanol(11.98 kg total mass) was charged to a vessel containing methyl(3S)-3-(2-methoxypyrimidin-5-yl)-5-oxo-6-(triphenylphosphoranylidene)hexanoate(Example 6; 4.84 kg). The resulting slurry was degassed, put under anatmosphere of nitrogen and then heated to reflux. The resulting clearsolution was aged for 12 hours. The reaction mixture was allowed to coolto room temperature overnight and directly used in Example 10 withoutisolation of the intermediate enone.

¹H NMR (250 MHz, CD₂Cl₂) δ 8.37 (s, 2 H), 7.46 (d, J=7.6 Hz, 1 H), 6.94(d, J=7.6 Hz, 1 H), 6.86 (dt, J=15.9, 6.7 Hz, 1 H), 6.06 (dt, J=15.9,1.5 Hz, 1 H), 3.94 (s, 3 H), 3.7-3.2 (br, 2H), 3.69-3.55 (m, 1 H), 3.57(s, 3 H), 3.02-2.81 (m, 4 H), 2.78-2.53 (m, 6 H), 1.88-1.75 (m, 2 H),1.72-1.55 (m, 2 H), 1.38 (s, 9H); ¹³C NMR (63 MHz, CD₂Cl₂) δ 197.5,171.9, 165.1, 158.9, 157.7, 155.5, 154.1, 147.5, 139.3, 132.5, 130.8,130.0, 121.6, 80.0, 55.1, 52.0, 47.2, 45.3, 40.1, 36.2, 33.5, 32.6,32.3, 29.9, 28.4, 26.4.

EXAMPLE 10 tert-Butyl2-[(7S)-8-methoxycarbonyl-7-(2-methoxypyrimidin-5-yl)-5-oxooctyl]-5,6,7,8-tetrahydropyrido[2,3-b]azepine-9-carboxylate

The solution of the enone intermediate of Example 9 in isopropanol wascharged to a hydrogenation vessel under an atmosphere of nitrogen. Aslurry of wet (58 wt % water) palladium on carbon catalyst (1.27 kg) inisopropanol (10 L) was added, washing with further isopropanol (15 L).After degassing the resulting reaction mixture was hydrogenated at 2.8bar for 2 hours. The catalyst was filtered and washed with isopropanol(4×15 L). The combined filtrates (88.0 kg) were concentrated underreduced pressure to a total volume of ca. 20 L and the solution wasdirectly used in Example 11 without isolation of the product.

¹H NMR (250 MHz, CD₂Cl₂) δ 8.37 (s, 2 H), 7.43 (d, J'7.6 Hz, 1 H), 6.92(d, J=7.6 Hz, 1 H), 3.93 (s, 3 H), 3.9-3.0 (br, 2 H), 3.66-3.52 (m, 1H),3.57 (s, 3 H), 2.90-2.62 (m, 7 H), 2.55 (dd, J=15.9, 8.7 Hz, 1 H),2.45-2.28 (m, 2 H), 1.86-1.75 (m, 2 H), 1.70-1.49 (m, 6 H), 1.37 (s,9H); ¹³C NMR (63 MHz, CD₂Cl₂) δ 208.2, 171.9, 165.1, 159.3, 158.9,155.3, 154.1, 139.1, 132.0, 130.0, 121.5, 79.9, 55.1, 52.0, 47.9, 47.1,43.3, 40.0, 37.6, 33.5, 32.0, 29.9, 29.5, 28.5, 26.5, 23.5.

EXAMPLE 11 tert-Butyl2-[(7S)-8-carboxy-7-(2-methoxypyrimidin-5-yl)-5-oxooctyl]-5,6,7,8-tetrahydropyrido[2,3-b]azepine-9-carboxylate

The solution of the BOC-protected methyl ester in isopropanol (ca. 20 L)from Example 10 (4.50 kg) was cooled to 0° C. 2M Sodium hydroxide (5.6L) was added and the resulting reaction mixture aged at 0° C. for 2hours. The resulting thin slurry was diluted with water (43 L) andwarmed to 20° C. The resulting aqueous solution was washed once withMTBE (43 L) and twice with IPAc (2×43 L). The aqueous layer was treatedwith 2M hydrochloric acid (0.56 L,) and IPAc (43 L) was then added. Theresulting biphasic solution was stirred and acidified with a secondportion of 2M hydrochloric acid (5.04 L,). The two layers were separatedand the aqueous phase (pH 3.8) was extracted with IPAc (43 L) and thecombined organic extracts washed with water (21 L). The resultingsolution was treated with Ecosorb™ C-941 (0.43 kg) and stirred for 1hour at room temperature. The mixture was filtered washing the filterbedwith IPAc (2×12 L). The filtrate was concentrated under reduced pressureto a total volume of ca. 20 L and the combined washes were then addedalong with a further portion of IPAc (16 L). The slurry was concentratedto a total volume of ca. 20 L and heptane (10 L) was added over a periodof 30 minutes, at room temperature. The resulting slurry was aged, andthen cooled to 0° C. The solids were then collected by filtration,washing with 2:1 IPAc:heptane (4.5 L). The off-white solid was driedunder vacuum, with a slight nitrogen purge, overnight at 45° C. toafford the BOC-protected intermediate (3.45 kg; 71% overall yield fromthe phosphorane intermediate).

¹H NMR (250 MHz, CD₂Cl₂) δ 9.8-8.9 (br, 1 H), 8.43 (s, 2 H), 7.49 (d,J=7.6 Hz, 1 H), 6.97 (d, J=7.6 Hz, 1 H), 4.2-2.5 (br, 2 H), 3.93 (s, 3H), 3.64 (app quintet, J=7.2 Hz, 1H), 2.94 (dd, J=17.4, 6.6 Hz, 1 H),2.78 (dd, J=17.2, 9.8 Hz, 1 H), 2.71-2.61 (m, 5 H), 2.56 (dd, J=15.7,7.6 Hz, 1 H), 2.45-2.29 (m, 2 H), 1.87-1.44 (m, 8 H), 1.35 (s, 9H); ¹³CNMR (63 MHz, CD₂Cl₂) δ 208.3, 173.8, 164.9, 159.2, 158.8, 154.8, 153.9,140.0, 132.6, 130.7, 122.0, 80.3, 55.2, 47.9, 47.1, 42.8, 40.6, 36.7,33.4, 32.2, 29.8, 29.6, 28.3, 26.3, 23.4.

EXAMPLE 12(3S)-3-(2-Methoxypyrimidin-5-yl)-5-oxo-9-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)nonanoicacid

The BOC-protected product of Example 11 (15 g) was dissolved indichloromethane (75 ml) and the solution cooled to 5° C. Trifluoroaceticacid (48.7 g) was added dropwise maintaining the internal temperature at<10° C. The reaction mixture was then heated to 30° C. and aged for ca.2 hours. The reaction mixture was then cooled to 0° C. and a 2M solutionof sodium hydroxide was added dropwise maintaining the temperature at orbelow ambient. The resulting solution was allowed to settle for ca. 1hour and the layers separated. The aqueous layer was treated withEcosorb™ C-941 (0.75 g) at ambient temperature for 1 hour. The resultingmixture was filtered through a bed of Hyflo™. The filter-bed was washedwith water (10 ml). The combined filtrates were acidified to pH 6.0 byadding concentrated hydrochloric acid (ca. 8 ml) whilst maintaining thetemperature at or below ambient temperature. The aqueous solution wasextracted with dichloromethane (2×150 ml) and the organics washed withwater (50 ml). The solution was solvent switched to isopropanol (65 ml)at atmospheric pressure and the solution warmed to 40° C., seeded with0.6% w/w seed, and maintained at 40° C. for 12 hours. Heating was thenremoved and the slurry allowed to cool to 20° C. Isolation by filtrationand washing with isopropanol (3×15 ml) afforded the title compound(9.0g, 74% yield).

¹H NMR (400 MH, DMSO-d₆) δ 8.34 (s, 2 H), 7.07 (d, J=7.4 Hz, 1 H), 6.31(d, J=7.4 Hz, 1 H), 3.79 (s, 3 H), 3.41-3.32 (m, 1 H), 3.01-2.96 (m, 2H), 2.79 (dd, J=17.1, 6.4 Hz, 1 H), 2.74 (dd, J=17.1, 7.8 Hz, 1 H),2.58-2.20 (m, 8 H), 1.65-1.52 (m, 4 H), 1.48-1.32 (m, 4H); ¹³C NMR (101MHz, DMSO-d₆) δ 209.3, 173.1, 165.0, 162.0, 159.3, 157.7, 139.5, 131.2,121.7, 113.8, 55.1, 47.9, 45.6, 43.1, 40.6, 37.3, 33.6, 32.6, 30.9,29.2, 27.1, 23.9.

EXAMPLE 13 Preparation of TRIS Salt of Compound of Formula (A) Where n=3

A slurry of the zwitterion of the compound of formula (A) where n=3(3.62 kg) and tris(hydroxymethyl)aminomethane (1.01 kg) in 2-propanol(35.7 L) and water (1.46 L) was heated to reflux to effect dissolution.The resulting solution was then cooled to 50° C. and seeded withauthentic TRIS salt of the compound of formula (A) where n=3 (3.0 g).The batch was aged for 1 h at 50° C. and then cooled to 20° C. over aperiod of 2 h. The resulting slurry was diluted with 2-propanol (25 L)and then concentrated under a partial vacuum at 35° C., to a volume of35 L. This procedure was repeated until the water content had reached<1.0% according to a Karl Fisher titration. Upon completion, the slurrywas cooled to 20° C. and the solids filtered. The wet cake was washedwith 2-propanol (1×20 L; 1×15 L) and dried overnight at 40° C. undervacuum to afford 4.40 kg of the TRIS salt (95% yield, 100 wt % pure) asa white solid.

1. A process for the preparation of a compound of formula (I)

comprising closing the ring of a compound of formula (II) with heat

wherein R¹ is hydrogen, chlorine, bromine or lower alkyl, P is an aminoprotecting group and n is 2 or 3, and Y is a group selected fromchlorine, bromine, iodine, mesylate, tosylate, brosylate, nosylate ortriflate.
 2. A process for the preparation of a compound of formula (I)

wherein R¹ is hydrogen, chlorine, bromine or lower alkyl, P is an aminoprotecting group and n is 2 or 3, comprising (a) reacting a compound offormula (III)

wherein R¹ and P are as previously defined and R³ is hydrogen or methyl,with a compound of the formula (IV)X—(CH₂)_(m)—Y   (IV) wherein Y is a group selected from chlorine,bromine, iodine, mesylate, tosylate, brosylate, nosylate, or triflate, Xis a group selected from chlorine, bromine, iodine, mesylate, tosylate,brosylate, nosylate, or triflate, and m is 3 or 4 when R³ is hydrogen,or m is 2 or 3 when R³ is methyl, to yield a compound of formula (II)

and (b) closing the ring of the compound of formula (II) with heat.
 3. Aprocess as claimed in claim 1 wherein R¹ is a chlorine atom.
 4. Aprocess as claimed in claim 3 wherein Y is a chlorine atom.
 5. A processas claimed in claim 4 wherein X is a bromine or iodine atom.
 6. Aprocess as claimed in claim 5 wherein the compound of formula (IV) isselected from Cl(CH₂)₄I, Cl(CH₂)₃I, Cl(CH₂)₂I, Cl(CH₂)₄Br, Cl(CH₂)₃Brand Cl(CH₂)₂Br.
 7. A process for the preparation of the compounds of theformulae (V) and (VI):

comprising reacting a compound of the formula (VII)

with an alkyllithium to form a reaction mixture, and reacting thereaction mixture with the compound of the formula (IV)X—(CH₂)_(m)—Y  (IV) wherein Y is a group selected from chlorine,bromine, iodine, mesylate, tosylate, brosylate, nosylate, and triflate,X is a group selected from chlorine, bromine, iodine, mesylate,tosylate, brosylate, nosylate, or triflate, and m is 3 or 4, to yield acompound of the formula (VIII)

wherein Y is as previously defined, and p is 3 or 4, and cyclizing thecompound of formula VIII, with heat, without isolation, to form thecompounds of formulae (V) and (VI).
 8. A process as claimed in claim 2wherein R¹ is a chlorine atom, Y is a chlorine atom, and X is a bromineor iodine atom.
 9. A process as claimed in claim 8 wherein the compoundof formula (IV) is selected from Cl(CH₂)₄I, Cl(CH₂)₃I, Cl(CH₂)₂I,Cl(CH₂)₄Br, Cl(CH₂)₃Br and Cl(CH₂)₂Br.
 10. A process as claimed in claim2 wherein n is 3 and P is selected from: tert-butylmethoxyphenylsilyl,tert-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, acetyl,pivaloyl (2,2-dimethyl-1-oxopropyl), o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, tert-butyloxycarbonyl(t-BOC), 2,2,2-trichloroethyloxycarbonyl, benzhydryl, o-nitrobenzyl,p-nitrobenzyl, 2-naphthylmethyl, benzyl, 2,2,2-trichloroethyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl,2-(trimethylsilyl)ethyl, p-methoxybenzyl, p-methoxyphenyl,4-pyridylmethyl, tert-butyl, allyloxycarbonyl, di-C₁₋₁₀ alkylphosphoryl,diarylphosphoryl and di-ar-C₁₋₁₀ alkylphosphoryl.